👤 Gunnar Th Gunnarsson

Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested "gene-negative" for familial predominantly pediatric CM, in hopes of finding a causative gene variant. 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with "gene-negative" results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed. Show less

The myosin-binding protein C ( We studied 60 probands with HCM caused by Genetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH-) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH- subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives. Phenotypic expression of the Icelandic Show less

Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium with variable expressivity and penetrance. Occasionally, homozygous sarcomere genetic variants emerge while genotyping HCM patients. In these cases, a more severe HCM phenotype is generally seen. Here, we report a case of HCM that was diagnosed clinically at 39 years of age. Initial symptoms were shortness of breath during exertion. Successively, he developed a wide array of severe clinical manifestations, which progressed to an ominous end-stage heart failure that resulted in heart transplantation. Genotype analysis revealed a missense MYBPC3 variant NM₀₀₀₂₅₆.3:c.2618C>A,p.(Pro873His) that presented in the homozygous form. Conflicting interpretations of pathogenicity have been reported for the Pro873His MYBPC3 variant described here. Our patient, presenting with two copies of the variant and devoid of a normal allele, progressed to end-stage heart failure, which supports the notion of a deleterious effect of this variant in the homozygous form. Show less

The geographic isolation and homogeneous population of Iceland are ideally suited to ascertain clinical and genetic characteristics of hypertrophic cardiomyopathy (HCM) at the population level. Medical records and cardiac imaging studies obtained between 1997 and 2010 were reviewed to identify Icelandic patients with HCM. Surviving patients were recruited for clinical and genetic studies. A previously identified Icelandic mutation, MYBPC3 c.927-2A>G, was genotyped, and mutation-negative samples were sequenced for HCM genes and other hypertrophic genes. Record review identified 180 patients with HCM. Genetic analyses of 151 patients defined pathogenic mutations in 101 (67%), including MYBPC3 c.927-2A>G (88 patients, 58%), 4 other MYBPC3 or MYH7 mutations (5 patients, 3.3%), and 2 GLA mutations (8 patients, 5.3%). Haplotype and genetic genealogical data defined MYBPC3 c.927-2A>G as a founder mutation, introduced into the Icelandic population in the 15th century, with a current population prevalence of 0.36%. MYBPC3 c.927-2A>G mutation carriers exhibited phenotypic diversity but were younger at diagnosis (42 versus 49 years; P=0.001) and sustained more adverse events (15% versus 2%; P=0.02) than mutation-negative patients. All-cause mortality for patients with HCM was similar to that of an age-matched Icelandic population (hazard ratio, 0.98; P=0.9). HCM-related mortality (0.78%/y) occurred at a mean age of 68 compared with 81 years for non-HCM-related mortality (P=0.02). A founder MYBPC3 mutation that arose >550 years ago is the predominant cause of HCM in Iceland. The MYBPC3 c.927-2A>G mutation is associated with low adverse event rates but earlier cardiovascular mortality, illustrating the impact of genotype on outcomes in HCM. Show less